Gossamer could put pressure on Merck
The pharma giant leads the pulmonary arterial hypertension pipeline, but other potentially disease-modifying treatments are in the works.
Following the hit in the pivotal Stellar trial, sotatercept is on course to become the first disease-modifying therapy for pulmonary arterial hypertension. At least, that’s what its developer Merck says – but there are several more projects in development for this rare disease that might give Merck a run for its money.
In terms of late-stage readouts the most immediate threat to Merck comes from United Therapeutics, an already entrenched PAH player with two further products in phase 3. But more innovative agents, designed to address the causes of the disease, are also in the works.
Pulmonary arterial hypertension is not simply high blood pressure in the lungs. It is a chronic disease that causes the walls of the arteries of the lungs to narrow and stiffen. This forces the right ventricle to work harder to pump blood through the lungs, and the extra stress causes heart disease.
Currently it is treated either with endothelin receptor antagonists, PDE 5 inhibitors, prostacyclin analogues or soluble guanylate cyclase stimulators, all of which fundamentally work as vasodilators. Many of the clinical-stage projects in development for PAH also ultimately work like this.
The next clinical project to report phase 3 data will be United Therapeutics’ ralinepag. This is a prostacyclin analogue – the same mechanism used by Johnson & Johnson’s PAH blockbuster Uptravi. Ralinepag is dosed once daily, offering a slight advantage over J&J’s twice-daily pill.
United is also working on a slightly more imaginative approach, though one that still focuses relaxing blood vessels rather than true disease modification. Aurora-GT is a gene therapy intended to deliver the gene for endothelial nitric oxide synthase, thereby increasing the patient’s levels of nitric oxide, a crucial vasodilator.
Administering this gene therapy involves isolating a PAH patient’s endothelial progenitor cells, transfecting the cells with the gene for endothelial nitric oxide synthase, expanding them ex-vivo and reintroducing them. The phase 3 Sapphire study will not report for a few years, and as Northern Therapeutics, which is majority-owned by United, is conducting the trial solely in Canada.
A great deal of buzz surrounds the second most advanced clinical project designed to treat the underlying causes of PAH – Gossamer Bio’s seralutinib. The molecule inhibits PDGFR α/β, colony stimulating factor 1 receptor and stem cell factor receptor (c-Kit), pathways believed to be responsible for the vascular remodelling seen in PAH.
Seralutinib is in an 80-patient phase 2 study, Torrey. Patients will take the inhaled drug for six months, with the primary and secondary endpoints being the change in pulmonary vascular resistance and six-minute walk distance, the same measures used in Merck’s successful trial of sotatercept.
SVB analysts wrote that if Torrey shows a decrease in vascular resistance of 20-30% and a 20-25m benefit on 6MWD for seralutinib over placebo, as well as decent safety, they would expect Gossamer’s shares to jump by about 30%.
One other project might also have the potential to change the course of PAH. Apabetalone is an epigenetic modifier, intended to prevent bromodomains from activating the expression of disease-associated genes. Resverlogix is developing it for cardiovascular disease and Covid as well as PAH.
Apabetalone has reversed pulmonary artery remodelling in various rat models of the PAH, according to researchers of its pilot trial, Approach-P. Resverlogix said the agent improved haemodynamic variables, including pulmonary vascular resistance, in this trial, but has not yet released full data. Its phase 2 study, Approach-2, has not yet started.
Should these projects succeed, there could be room for seralutinib, sotatercept and perhaps even apabetalone in PAH, since they target distinct pathways. Merck has the first-mover advantage; when the full data from Stellar are released it could become clear exactly how much this is worth.
|The PAH pipeline|
|Sotatercept*||Merck & Co/
Bristol Myers Squibb
|Activin receptor 2a regulator||Ph3 pivotal Stellar trial hit Oct 2022
Ph3 Zenith trial in high-risk patients to report 2025
Ph3 Hyperion trial in newly diagnosed pts to report 2028
|Ralinepag||United Therapeutics||Prostacyclin analogue||Ph3 Advance Outcomes trial to report early 2023|
|MK-5475||Merck & Co||Inhaled guanylate cyclase stimulator||Ph2/3 Insignia-PAH trial to report 2024|
|Aurora-GT||United Therapeutics||Endothelial nitric oxide synthase gene therapy||Ph2/3 Sapphire trial to report 2025|
|AV-101*||Aerovate Therapeutics||Bcr/Abl fusion protein inhibitor||Ph2/3 Impahct trial to report 2025
Ph2/3 Impahct-ful extension trial to report 2026
|Gossamer Bio||PDGFR, CSF1R and c-Kit inhibitor||Ph2 Torrey trial to report topline data Nov/Dec 2022|
|CS1*||Cereno Scientific||HDAC inhibitor||Ph2 trial to report early 2023|
|Insmed||Prostacyclin analogue||Ph2 trial to report 2024|
|Apabetalone*||Resverlogix||Bromodomain inhibitor||Ph2 Approach-2 trial not yet recruiting; to report 2025|
|CAM2043||Camurus||Prostacyclin analogue||Ph1 pharmacokinetics trial complete; no trials in PAH pts yet conducted|
|RemoPro||United Therapeutics||PPAR-delta agonist; prostacyclin analogue||Ph1 trials under way according to pipeline|
|*Potentially disease-modifying; all others are essentially vasodilators. Source: Evaluate Pharma, clinicaltrials.gov, company websites.|
This article was updated on November 15, 2022 to include projects from Aerovate Therapeutics and Cereno Scientific.